The invention pertains to lyophilized ifosfamide, solutions thereof, and methods of preparing and using lyophilized ifosfamide.
Ifosfamide is a chemotherapeutic agent of the formula: 
and is described in U.S. Pat. No. 3,732,340. Ifosfamide is sometimes referred to as N,3-bis(2-chloroethyl) tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide, and 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide. Ifosfamide has the molecular formula C7H15Cl2N2O2P, and has a molecular weight of 261.1. Ifosfamide is manufactured as a white crystalline powder, which has a melting point of about 48-51xc2x0 C. and which is highly hygroscopic. Ifosfamide begins to sinter at temperatures below its melting point and, therefore, must be stored at relatively low temperatures (room temperature or below). In addition, contact with moisture in the air should be avoided whenever possible. Ifosfamide dissolves in water to the extent of at least about 10 wt %, but has limited stability in an aqueous solution (reported in some references as about 3-4 hours at 20-22xc2x0 C., or 36 hours at 4-6xc2x0 C.).
Ifosfamide is approved in the U.S. for third-line chemotherapy of germ cell testicular cancer and is ordinarily used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna. Ifosfamide is presently marketed in the U.S. under the name IFEX(copyright), which is supplied as a crystalline powder and is stored in 1 g and 3 g single dose vials. For therapeutic applications, the powder is dissolved in a sterile aqueous vehicle such as Sterile Water for Injection, USP; or a sterile aqueous vehicle that contains a bacteriostat, e.g., Sterile Bacteriostatic Water for Injection, USP (preserved with benzyl alcohol or parabens), and is administered by injection. Typically, the 1 g and 3 g dosage forms are constituted in 20 mL and 60 mL of the aqueous vehicle, respectively, to achieve a final concentration of 50 mg/mL. Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6-20 mg/mL in injectable fluids such as 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Lactated Ringer""s Injection, USP; or Sterile Water for Injection, USP.
Ifosfamide is normally administered intravenously at a dosage of about 1.2 g/m2 per day for five consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. The duration of the infusion is generally about 30 minutes, but may be 1 to 2 hours. Ifosfamide solutions should be refrigerated and be used within 24 hours. See, e.g., Physicians"" Desk Reference, 56th Ed., Medical Economics Co., Inc., Montvale, N.J., pp. 1123-1124 (2002).
The manufacture of ifosfamide sterile powder involves a powder fill operation that presents a number of practical problems. During the production of the sterile powder, the powder is processed in a way that causes variations in the flow properties. The variation in flow properties greatly impairs the accuracy of dosage during the filling process. The sterile powder fill operation further employs specialized equipment. The powder fill operation is costly and may be further complicated by the risk of microbial contamination during the operation. Moreover, the powder fill process creates risks of accidental exposure to the powder by personnel that are involved in the production process. The processing and storage of ifosfamide powder is still further complicated by its hygroscopic properties, sensitivity to heat, and relatively low melting point. If the powder is stored for a long period of time, the product sinters and its dissolution time increases significantly.
Various approaches for manufacturing lyophilized forms of ifosfamide have been proposed. For example, U.S. Pat. Nos. 5,750,131 and 5,972,912 describe the lyophilization of one or more amino acids in combination with ifosfamide. U.S. Pat. No. 5,204,335 describes the lyophilization of hexitols in combination with ifosfamide, and U.S. Pat. No. 4,959,215 describes the lyophilization of hexitols in combination with ifosfamide/mesna mixtures. In addition, U.S. Pat. No. 5,227,373 describes the lyophilization of urea in combination with ifosfamide.
While the lyophilization processes described above overcome some of the problems associated with the crystalline powder, such processes are disadvantageous in that they utilize auxiliary materials such as amino acids, hexitols and urea, are not present in the product that is approved for human chemotherapy. Thus, there remains a need for a stable, sterile form of lyophilized ifosfamide that contains no auxiliary materials, and methods of producing such a product. The invention provides such a product and production processes. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides a stable, sterile, pharmaceutical product that consists essentially of lyophilized ifosfamide. The lyophilized ifosfamide of the present invention is preferably contained in within a container that is aseptically sealed. Preferably, the container contains a therapeutically effective amount of the ifosfamide of the present invention and is of sufficient volume to contain the volume of solution that is recommended for constitution. The present invention further provides a solution prepared by dissolving the lyophilized ifosfamide of the present invention in an aqueous vehicle, such as a sterile aqueous solvent that is suitable for injection.
The present invention further provides a method of producing lyophilized ifosfamide, which method includes freezing a sterile aqueous solution of ifosfamide to produce a frozen mixture;
subjecting the frozen mixture to a primary drying stage, which includes applying a vacuum to reduce the pressure by an amount or to a level that is effective to remove the aqueous solvent from the frozen mixture, and, while applying the vacuum, raising the temperature to a primary drying temperature, to produce a first intermediate; and
subjecting the first intermediate to a secondary drying stage, which includes applying a vacuum to reduce the pressure by an amount or to a level that is effective to remove the aqueous solvent from the first intermediate, and, while applying the vacuum, raising the temperature to a secondary drying temperature, to produce the pharmaceutical product.
The method of the present invention can be applied toward the production of stable, sterile, essentially pure dosage forms of ifosfamide (e.g., a sterile single-dose ifosfamide product), which method includes:
filling one or more containers, each container defining an opening, with a sterile solution consisting essentially of a therapeutically effective amount of ifosfamide and an aqueous solvent;
subjecting the sterile solution in the one or more containers to the present method of producing lyophilized ifosfamide; and
sealing the opening of the one or more containers, to produce the pharmaceutical product.
The dosage form prepared in accordance with the present invention preferably contains a dosage that is within about 5% of the label claim. The lyophilized ifosfamide of the present invention can be administered to a patient using standard therapeutic methods for delivering ifosfamide (e.g., by injection).
The present invention provides a stable, sterile, pharmaceutical product that consists essentially of lyophilized ifosfamide. The lyophilized ifosfanlide of the present invention is a white to off-white solid of high purity and has a low moisture content. The lyophilized ifosfamide of the present invention is preferably greater than 98% pure (i.e., contains less than 2% total impurities based on the total weight of ifosfamide), and is more preferably greater than 99% pure (i.e., contains less than about 1% impurities). Preferably, the lyophilized ifosfamide of the present invention has a moisture content of less than about 1 wt % (% water based on the weight of ifosfamide). More preferably the moisture content is about 0.8 wt % or less, and still more preferably is about 0.5 wt % or less. Most preferably, the lyophilized ifosfamide of the present invention has a moisture content of about 0.3 wt % or less.
The lyophilized ifosfamide of the present invention can be contained within a sealed container. Preferably, the lyophilized ifosfamide of the present invention is contained within a container that is sealed aseptically. More preferably, the container is provided with an opening and a means for aseptically sealing the opening, e.g., such that the sealed container is fluidly sealed or the sealed opening is substantially impermeable to atmospheric gasses, moisture, pathogenic microorganisms, or the like. The container can be constructed of any suitable material such as, for example, glass, polypropylene, Daikyo Resin CZ (sold by Daikyo Gomu Seiko, Ltd.), polyethylene terephthalate, and the like. In a preferred embodiment, the container is constructed of glass. Suitable glass containers include, but are not limited to, glass vials. Suitable glass vials include molded glass vials such as, for example, Type I molded glass vials, and the like. Such molded glass vials can be obtained from Kimble Glass, Inc., Vineland, N.J.; Wheaton Science Products, Miliville, N.J., or other companies.
A suitable means for sealing the container can include, for example, a stopper, a cap, a lid, a closure, a covering which fluidly seals the container, or the like. Examples of suitable closures include closures that are suitable for medical vials, such as those described in U.S. Pat. No. 4,671,331 and references cited therein. The means for sealing the container are not limited to separate closures or closure devices, but also includes self-sealing containers and containers which are manufactured and sealed during filling operations. In a preferred embodiment, the means for aseptically sealing the container includes a stopper such as, for example, a stopper that is configured to fluidly seal the opening. Suitable stoppers include conventional medical grade stoppers which do not degrade or release significant amounts of impurities upon exposure to the constituted aqueous ifosfamide solution. Preferably, the stopper is constructed of an elastomer, which is more preferably an elastomer that is pierceable by a hypodermic needle or a blunt cannula. Exemplary stoppers include 6720 GC gray rubber stoppers from American Stelmi Corporation, 4432/50 gray rubber stoppers from West Company, and the like.
Optionally, an outer seal is provided which covers and entirely surrounds the stopper. The outer seal can be constructed of any suitable material. When an outer seal is used, it is preferably fitted with a lid that can be easily manually removed to provide access to the stopper. Suitable outer seals can include, for example, Flip-off Aluminum/Polypropylene Seals (lacquered or non-lacquered aluminum), marketed by The West Company, Inc., and other manufacturers. Such seals include an outer rim made of a suitable material, such as aluminum, that entirely surrounds the lateral edge of the stopper and further include a lid (typically polypropylene or other suitable material) that entirely covers the upper surface of the stopper. The polypropylene lid can be xe2x80x9cflippedxe2x80x9d off e.g., by exerting upward pressure with a finger or thumb, to provide access to the stopper which, in turn, provides access to the stopper, e.g., so that it can be punctured with a hypodermic needle to deliver an aqueous vehicle for constitution. See, e.g., U.S. Pat. No. 6,136,814.
Preferably, the container contains a therapeutically effective dose of the ifosfamide of the present invention and is of sufficient volume to contain the volume of solution that is recommended for constitution. More preferably, the container contains ifosfamide in an amount which is an approved dosage for human chemotherapy and is of sufficient volume to contain the total volume of solution recommended for constitution. In a particularly preferred embodiment, the container volume is about 30 mL, and about 1.0 g of the lyophilized ifosfamide of the present invention are contained within the container. In another particularly preferred embodiment, the container volume is about 100 mL, and about 3.0 g of lyophilized ifosfamide of the present invention are contained within the container.
The present invention includes solutions prepared by dissolving the lyophilized ifosfamide manufactured in accordance with the method of the present invention dissolved in an aqueous vehicle. The aqueous vehicle is preferably a sterile aqueous vehicle that is normally used as liquid vehicle for injection. Suitable aqueous vehicles include, for example, sterile water (e.g., Sterile Water for Injection, USP) and sterile aqueous vehicles that contain a bacterial growth inhibiting-effective amount of one or more bacteriostatic agents, e.g., Sterile Bacteriostatic Water for Injection, USP (preserved with benzyl alcohol or parabens), as described herein, and the like.
The present invention further provides a method of producing the lyophilized ifosfamide of the present invention, which method includes freezing a sterile aqueous solution, to produce a frozen mixture;
subjecting the frozen mixture to a primary drying stage, which includes applying a vacuum to reduce the pressure by an amount or to a level that is effective to remove aqueous solvent from the frozen mixture, and, while applying the vacuum, raising the temperature to a primary drying temperature, to produce a first intermediate; and
subjecting the first intermediate to a secondary drying stage, which includes applying a vacuum to reduce the pressure by an amount that is effective to remove aqueous solvent from the first intermediate, and, while applying the vacuum, raising the temperature to a secondary drying temperature, to produce the pharmaceutical product.
The sterile solution preferably consists essentially of ifosfamide and an aqueous solvent. The sterile solution can have an ifosfamide concentration up to about 130 mg/mL or even greater, but more typically has a concentration of about 130 mg/mL or less (e.g., from about 10 mg/mL to about 130 mg/mL). Preferably, the sterile solution has a concentration of about 100 mg/mL or less (e.g., from about 10-100 mg/mL), but more preferably has a concentration of from about 30-100 mg/mL, and still more preferably has a concentration of from about 50-100 mg/mL. In a particularly preferred embodiment, the sterile solution has a concentration of about 100 mg/mL.
The sterile solution is xe2x80x9cfrozenxe2x80x9d or cooled to a temperature that freezes the aqueous solvent. Preferably, the sterile solution is frozen sufficiently to allow for its removal under reduced pressure (e.g., by sublimation). Preferably, the sterile solution is frozen to a temperature of about xe2x88x9210xc2x0 C. or lower (e.g., from about xe2x88x9210xc2x0 C. to about xe2x88x9270xc2x0 C., from about xe2x88x9220xc2x0 C. to about xe2x88x9270xc2x0 C., from about xe2x88x9230xc2x0 C. to about xe2x88x9270xc2x0 C., or from about xe2x88x9230xc2x0 C., to about xe2x88x9260xc2x0 C.), but is more preferably frozen to a temperature of about xe2x88x9240xc2x0 C. or lower (e.g., from about xe2x88x9240xc2x0 C. to about xe2x88x9260xc2x0 C.). Most preferably, the sterile solution is frozen to a temperature of about xe2x88x9250xc2x0 C. or lower (e.g., from about xe2x88x9250xc2x0 C. to about xe2x88x9260xc2x0 C.).
The sterile solution can be frozen rapidly (e.g., by contacting a container of the solution in a cooling bath), or by cooling in stages (e.g., by lowering the temperature incrementally at progressively lower temperatures until the frozen mixture is obtained). Alternatively, the sterile solution can be frozen by continuously cooling at a substantially constant rate until the frozen mixture is obtained. For example, the sterile solution can be frozen by cooling at a substantially constant rate of about 5xc2x0 C. per minute or less (e.g., from about 0.1-5xc2x0 C. per minute), at a rate of about 3xc2x0 C. per minute or less (e.g., from about 0.1-3xc2x0 C. per minute), at a rate of about 2xc2x0 C. per minute or less (e.g., from about 0.1-2xc2x0 C. per minute), or at a rate of about 1xc2x0 C. per minute or less (e.g., from about 0.1-1xc2x0 C. per minute, or from about 0.1-0.5xc2x0 C. per minute), until the frozen mixture is obtained. Alternatively, the sterile solution can be frozen using a combination of incremental cooling stages and one or more continuous cooling cycles (e.g., continuously cooling at a substantially constant rate) until the frozen mixture is obtained.
The primary drying temperature is preferably from about xe2x88x9240xc2x0 C. to about 25xc2x0 C., but is more preferably from about xe2x88x9230xc2x0 C. to about 15xc2x0 C., and is even more preferably from about xe2x88x9220xc2x0 C. to about 10xc2x0 C., and is still more preferably from about xe2x88x9215xc2x0 C. to about 0xc2x0 C. Most preferably, the primary drying temperature is from about xe2x88x9215xc2x0 C. to about xe2x88x925xc2x0 C. (e.g., about xe2x88x9210xc2x0 C.). In the primary drying stage, the temperature can be raised in stages (e.g., raised incrementally at progressively higher temperatures until the primary drying temperature is attained). Alternatively, the temperature of the primary drying stage can be raised continuously (e.g., at a substantially constant rate) until the primary drying temperature is attained. Preferably, the temperature of the primary drying stage is raised at a rate of about 5xc2x0 C. per minute or less (e.g., from about 0.1-5xc2x0 C. per minute). More preferably, the temperature of the primary drying stage is raised at a rate of about 3xc2x0 C. per minute or less (e.g., from about 0.1-3xc2x0 C. per minute). Still more preferably, the temperature of the primary drying stage is raised at a rate of about 2xc2x0 C. per minute or less (e.g., from about 0.1-2xc2x0 C. per minute). Most preferably, the temperature of the primary drying stage is raised at a rate of about 1xc2x0 C. per minute or less (e.g., from about 0.1-1xc2x0 C. per minute, or from about 0.1-0.5xc2x0 C. per minute). In a particularly preferred embodiment, the temperature in the primary drying stage is raised at a rate of about 0.5xc2x0 C. per minute or less (e.g., about 0.5xc2x0 C. per minute, or about 0.2xc2x0 C. per minute).
The primary drying temperature in the primary drying stage is preferably maintained (e.g., held at a substantially constant temperature or kept within a particular range) until substantially all of the aqueous solvent is removed. The removal of substantially all of the aqueous solvent can be determined by visual inspection. Alternatively, the removal of substantially all of the aqueous solvent can be determined on the basis of when the increase in the temperature of the frozen mixture (internal temperature) becomes insignificant. Normally, as the temperature is raised during the primary drying stage, the internal temperature xe2x80x9clagsxe2x80x9d behind (i.e., is lower than) the external temperature (sometimes referred to as the xe2x80x9cshelf temperaturexe2x80x9d). In some instances when the external temperature is raised during the primary drying stage, the internal temperature can lag behind the external temperature by as much as about 10xc2x0 C., or even more. Typically, the removal of substantially all of the solvent can be determined by comparing the internal temperature with the external temperature. The temperature of the frozen mixture and the external temperature can be measured using any suitable means, e.g., a thermometer, a thermocouple, or the like. In most instances, substantially all of the aqueous solvent is removed when the internal temperature remains steady or is about equal to (e.g., is slightly less than, is equal to, or slightly exceeds) the external temperature. In a preferred embodiment, the primary drying temperature is maintained until the temperature of the frozen mixture is about equal to the primary drying temperature.
The secondary drying temperature in the secondary drying stage can range from about 0xc2x0 C. to about 40xc2x0 C., but is preferably from about 10xc2x0 C. to about 40xc2x0 C. More preferably, the secondary drying temperature is about ambient temperature (e.g., from about 15xc2x0 C. to about 30xc2x0 C.), which is still more preferably from about 20-30xc2x0 C., and is most preferably from about 20-25xc2x0 C. (e.g., about 25xc2x0 C.). In the secondary drying stage, the temperature can be raised at a rate which is the same or different than the rate at which the temperature is raised in the primary drying stage. For example, the temperature in the secondary drying stage can be raised in stages (e.g., raised incrementally at progressively higher temperatures until the secondary drying temperature is attained). Alternatively, the temperature in the secondary drying stage can be raised continuously (e.g., at a substantially constant rate) until the secondary drying temperature is attained. Preferably, the temperature of the secondary drying stage is raised at a rate of about 5xc2x0 C. per minute or less (e.g., from about 0.1-5xc2x0 C. per minute). More preferably, the temperature of the secondary drying stage is raised at a rate of about 3xc2x0 C. per minute or less (e.g., from about 0.1-3xc2x0 C. per minute). Still more preferably, the temperature of the secondary drying stage is raised at a rate of about 2xc2x0 C. per minute or less (e.g., from about 0.1-2xc2x0 C. per minute). Most preferably, the temperature of the primary drying stage is raised at a rate of about 1xc2x0 C. per minute or less (e.g., from about 0.1-1xc2x0 C. per minute, or from about 0.1-0.5xc2x0 C. per minute). In a particularly preferred embodiment, the temperature in the primary drying stage is raised at a rate of about 0.50xc2x0 C. per minute or less (e.g., about 0.5xc2x0 C. per minute, or about 0.20xc2x0 C. per minute).
Preferably, the secondary drying temperature in the secondary drying stage is maintained until the moisture content is less than about 1 wt % relative to the ifosfamide. More preferably, the secondary drying temperature in the secondary drying stage is held until the moisture content is about 0.5 wt % or less relative to the ifosfamide. Most preferably, the secondary drying temperature in the secondary drying stage is held until the moisture content is about 0.3 wt % or less relative to the ifosfamide.
The primary drying stage is preferably carried out at a pressure of about 1 Torr (1000 mTorr, 133 Pa) or less, e.g., from about 10-1000 mTorr (1.33-133 Pa), but is more preferably carried out at a pressure of about 500 mTorr (66.7 Pa) or less, e.g., from about 10-500 mTorr (1.33-66.7 Pa). Still more preferably, the primary drying stage is carried out at a pressure of about 200 mTorr (26.7 Pa) or less, e.g., from about 10-200 mTorr (1.33-26.7 Pa). Most preferably, the primary drying stage is carried out at a pressure of about 150 mTorr (20 Pa) or less, e.g., from about 10-150 mTorr (1.33-20 Pa). In a particularly preferred embodiment, the primary drying stage is carried out at a pressure of about 100 mTorr (13.3 Pa) or less, e.g., from about 10-100 mTorr (1.33-13.3 Pa).
The secondary drying stage can be carried out at a pressure which is the same or different than the pressure at which the primary drying stage is carried out. Preferably, the secondary drying stage is carried out at a pressure of about 1 Torr (1000 mTorr, 133 Pa) or less, e.g., from about 10-1000 mTorr (1.33-133 Pa), but is more preferably carried out at a pressure of about 500 mTorr (66.7 Pa) or less, e.g., from about 10-500 mTorr (1.33-66.7 Pa), and is still more preferably carried out at a pressure of about 200 mTorr (26.7 Pa) or less, e.g., from about 10-200 mTorr (1.33-26.7 Pa). Most preferably, the secondary drying stage is carried out at a pressure of about 150 mTorr (20 Pa) or less, e.g., from about 10-150 mTorr (1.33-20 Pa). In a particularly preferred embodiment, the secondary drying stage is carried out at a pressure of about 100 mTorr (13.3 Pa) or less, e.g., from about 10-100 mTorr (1.33-13.3 Pa).
The method of the present invention can be applied toward the production of stable, sterile, essentially pure dosage forms of ifosfamide (e.g., sterile single-dose or multiple-dose ifosfamide products). Exemplary pharmaceutical dosage forms include a pharmaceutical dosage form comprising a sealed container (e.g., a container as described herein) and a pharmaceutical product consisting essentially of a therapeutically effective amount of lyophilized ifosfamide contained within the container. The pharmaceutical dosage form of the present invention preferably includes a dose of about 1.0 g or about 3.0 g of the lyophilized ifosfamide contained within the container.
The method of the present invention can consistently and reproducibly produce dosage forms with high dosage accuracy and low variability in the dosage. Moreover, the method of the present invention is simpler and is significantly less costly than the conventional methods used in the production of ifosfamide crystalline powder. In one aspect, the present invention includes a method of producing a stable, sterile pharmaceutical product consisting essentially of lyophilized ifosfamide, which includes:
filling one or more containers with a sterile solution consisting essentially of a therapeutically effective amount of ifosfamide and an aqueous solvent, each container defining an opening;
subjecting the sterile solution in the one or more containers to the lyophilized ifosfamide production method described herein; and
sealing the opening of the one or more containers, to produce the pharmaceutical product.
The method of the present invention preferably includes:
aseptically filling one or more containers, each container defining an opening, with a sterile solution consisting essentially of a therapeutically effective amount of ifosfamide and an aqueous solvent;
freezing the sterile solution in the one or more containers, to produce a frozen mixture;
subjecting the frozen mixture to a primary drying stage, which includes applying a vacuum to reduce the pressure by an amount effective to remove aqueous solvent from the frozen mixture, and, while applying the vacuum, raising the temperature to a primary drying temperature, to produce a first intermediate; and
subjecting the first intermediate to a secondary drying stage, which comprises applying a vacuum to reduce the pressure by an amount effective to remove aqueous solvent from the first intermediate, and, while applying the vacuum, raising the temperature to a secondary drying temperature, to produce a sterile solid consisting essentially of ifosfamide in the one or more containers; and
aseptically sealing the opening(s) of the one or more containers, to produce the pharmaceutical product,
wherein the frozen mixture, the primary and secondary drying stages, and the one or more containers are as described herein.
The one or more containers preferably include one or more sterile vials, preferably glass vials, as described herein. The sealing step preferably includes sealing the opening using the means for aseptically sealing the opening described herein. The sealing means preferably includes a stopper as described herein. The sterile solution preferably has an ifosfamide concentration of about 130 mg/mL or less, more preferably about 100 mg/mL or less. In a particularly preferred embodiment, the concentration of the sterile solution is about 100 mg/mL and the one or more containers (which are most preferably vials) are filled with 10.0 mL or 30.0 mL of the sterile solution, to provide a final dosage of 1.0 g or 3.0 g of ifosfamide, respectively.
The dosage form prepared in accordance with the present invention preferably is within about 5% of the label claim. In other words, the amount of ifosfamide in the container (as determined by a suitable analytical technique, e.g., HPLC, ifosfamide assay, or the like) preferably is within about 5 wt % of the ifosfamide dosage claimed in product label. By way of example, for 1 g dosage vials prepared in accordance with the present invention, with a label claim of 1.0 g of ifosfamide, the amount of ifosfamide in the vials, as determined by a suitable analytical technique, preferably is within about 0.95-1.05 g. For 3.0 g dosage vials prepared in accordance with the present invention, with a label claim of 3.0 g of ifosfamide, the amount of ifosfamide in the vials, as determined by a suitable analytical technique, preferably is within about 2.85-3.15 g. More preferably, the product prepared in accordance with the present invention has an actual dosage that is within about 4% of the label claim. Most preferably, the product prepared in accordance with the present invention has an actual dosage that is within about 3% of the label claim.
The lyophilized ifosfamide of the present invention can be administered to a patient in need thereof (e.g., for chemotherapy) using standard therapeutic methods for delivering ifosfamide including, but not limited to, the methods described herein. The lyophilized ifosfamide of the present invention is preferably administered by dissolving a therapeutically effective amount of the lyophilized ifosfamide of the present invention in a pharmaceutically acceptable solvent to produce a pharmaceutically acceptable solution, and administering the solution (preferably by injection) to the patient.
The lyophilized ifosfamide of the present invention may be constituted for parenteral administration to a patient using any pharmaceutically acceptable diluent. Preferably, the diluent is Sterile Water for Injection, USP. Alternatively, Sterile Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved) may be used as a diluent. Any quantity of diluent may be used to constitute the lyophilized ifosfamide such that a suitable solution for injection is prepared. Accordingly, the quantity of diluent must be sufficient to dissolve the lyophilized ifosfamide. Typically, 20-60 mL of diluent are used to constitute the lyophilized ifosfamide to yield a final concentration of about 50 mg/mL. Constituted solutions of lyophilized ifosfamide should be administered to a patient promptly upon constitution. Alternatively, constituted solutions may be refrigerated and used within 24 hours.
Solutions of ifosfamide may be further diluted after constitution to achieve concentrations of about 0.6 to about 20 mg/mL. Suitable fluids for further dilution of solutions of constituted lyophilized ifosfamide include, by way of example, 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, Lactated Ringer""s Injection USP, and Sterile Water for Injection USP.